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Dose Escalation of Oral Vinorelbine in Combination with Estramustine in Hormone-Refractory Adenocarcinoma of the Prostate

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Dose Escalation of Oral Vinorelbine in Combination with Estramustine in Hormone-Refractory Adenocarcinoma of the Prostate 2617 Dose Escalation of Oral Vinorelbine in Combination with Estramustine in Hormone-Refractory Adenocarcinoma of the Prostate 1 Niklas J. Mackler, M.D. BACKGROUND. The primary objective of the current study was to identify the 2 Rodney L. Dunn, M.S. tolerable dose level of oral vinorelbine when given in combination with estramus- 1 Beth Hellerstedt, M.D. tine to men with hormone-refractory prostate cancer (HRPC). The secondary 1,2 Kathleen A. Cooney M.D. objectives were to describe the toxicities of the combined regimen in patients with 1 Judith Fardig, P.A.-C. HRPC and to estimate the efficacy of oral vinorelbine in combination with estra- 1 Karin Olson, P.A.-C. mustine based on the prostate-specific antigen (PSA) response. 1,2 Kenneth J. Pienta, M.D. METHODS. Thirty-three patients with HRPC were treated on a 28-day cycle with 1,2 David C. Smith, M.D. estramustine at a dose of 140 mg orally 3 times a day on Days 1-3 and 8-10. Vinorelbine was given orally on Days 2 and 9. The initial dose of vinorelbine was 1 Division of Hematology/Oncology, Department of 50 mg/m2 and was escalated to 70 mg/m2 using the time-to-event continual Internal Medicine, University of Michigan School of reassessment method. Medicine, Ann Arbor, Michigan. RESULTS. Three of 17 patients experienced dose-limiting toxicity at the 70 mg/m2 2 University of Michigan Comprehensive Cancer dose level of oral vinorelbine. One patient experienced dose-limiting toxicity at a Center, University of Michigan, Ann Arbor, Michi- dose of 60 mg/m2 and no dose-limitig toxicities were reported at the 50 mg/m2 gan. dose. The overall response rate by Ն50% reduction in PSA was 17.2%, (95% confidence interval, 5.9-35.8%). CONCLUSIONS. Oral vinorelbine at doses of 70 mg/m2 may be safely combined with estramustine. The combination appears to have modest activity in men with advanced prostate cancer. The trial design employed the time-to-event continual reassessment method, which potentially allows for rapid accrual, a more complete assessment of toxicities, and a larger fraction of patients to be treated at an effective dose. More active regimens are needed to further evaluate the utility of this clinical trial design in patients with prostate cancer. Cancer 2006;106:2617–23. © 2006 American Cancer Society. KEYWORDS: prostate cancer, Phase I trials, biochemical resistant, clinical trials, adult medical oncology. Supported in part by Grant 2P30 CA 46592-14 from the National Cancer Institute and the National denocarcinoma of the prostate is the second leading cause of 1 Institutes of Health and a grant from GlaxoSmith- Adeath from neoplasia in men. Roughly 50% of men will recur with Kline. advanced disease after definitive local therapy and most are effec- tively treated with androgen ablation. The duration of response to Presented in part at the 39th annual meeting of the androgen ablation is limited, however, with most patients developing American Society of Clinical Oncology, Chicago, Illinois, May 30–June 3, 2003. disease recurrence with hormone-refractory prostate cancer (HRPC). Responses to secondary hormonal therapies are typically short-lived Address for reprints: David C. Smith, M.D., 7302 and remain only a temporary option. In general, chemotherapy for CCGC 0946, 1500 E. Medical Center Dr., Ann HRPC has been considered to be palliative, although recent studies Arbor, MI 48109; Fax: (734) 615-2719; E-mail: have shown improvements in survival and quality of life.2–5 [email protected] A number of chemotherapy agents that block the microtubule Received November 14 2005; revision received apparatus have been evaluated in combination or as single agents in January 19 2006; accepted February 2 2006. HRPC. Estramustine (Emcyt; Pfizer, Groton, CT), a nor-nitrogen mus- © 2006 American Cancer Society DOI 10.1002/cncr.21927 Published online 11 May 2006 in Wiley InterScience (www.interscience.wiley.com). 2618 CANCER June 15, 2006 / Volume 106 / Number 12 tard linked to an estrogen, has been used in combi- alkaloid-based cytotoxic chemotherapy or radiation to nations with taxanes and vinca alkaloids to create Ն50% of the total bone marrow or if they had evidence complementary inhibition of microtubule assembly of brain metastasis or untreated spinal cord compres- and function.6–8 Estramustine binds to microtubule- sion. No prior malignancy except for in situ carci- associated proteins, inhibiting microtubule assembly. noma, nonmelanoma skin cancer, or adequately Vinorelbine (Navelbine; GlaxoSmithKline, Philadel- treated malignancy that had been inactive for Ͻ3 phia, PA), a vinca alkaloid, inhibits mitosis at meta- years was allowed. Patients with preexisting neuropa- phase through interaction with tubulin. In contrast to thy ՆGrade 2, active gastrointestinal disease, or a dis- other vinca alkaloids, vinorelbine appears to bind order that altered gastrointestinal motility or absorp- preferentially to the mitotic spindle, with lesser effects tion were also excluded. The Institutional Review on the microtubules in neural structures.9 Board of the University of Michigan Medical School In a Phase II trial of 25 patients with metastatic (Ann Arbor, MI) reviewed and approved the trial and prostate cancer using the combination of intravenous the informed consent document. Written informed vinorelbine and estramustine, 9 patients had a Ͼ65% consent was obtained from all patients before enroll- decline in prostate-specific antigen (PSA), whereas ment in the study. Data and safety monitoring were 10 patients had stable disease. Toxicities were mini- conducted under the criteria of the National Cancer mal and included alopecia, nausea/vomiting, and Institute (NCI)-approved plan for the University of anorexia.10 A second Phase II trial of this combination Michigan Comprehensive Cancer Center. demonstrated a Ն50% decline in PSA in 15 of 21 patients with HRPC. The most frequent adverse events Trial Design were edema and thromboembolic complications.11 All patients were treated and followed as outpatients Oral vinorelbine is a newer formulation. A Phase II at the University of Michigan Comprehensive Cancer evaluation of oral vinorelbine in locally advanced or Center. The trial utilized a time-to-event continual metastatic breast cancer demonstrated response rates reassessment method (TITE-CRM) design13–15 for the of 30%. The main adverse events were neutropenia dose escalation of vinorelbine. TITE-CRM was used to and gastrointestinal disorders. The efficacy and toxic- monitor the trial by estimating the rate of dose-limit- ity profiles of the oral formulation appeared to com- ing toxicity (DLT) while optimizing the number of pare favorably with those of intravenous vinorelbine.12 patients treated at effective doses and maintaining We conducted a Phase I trial to determine the open trial enrollment. The primary endpoint was to tolerable dose of oral vinorelbine in combination with identify the oral vinorelbine level associated with tox- oral estramustine on an intermittent schedule in pa- icity in 30% of patients when given in combination tients with HRPC. The secondary objective of the with oral estramustine. Secondary endpoints included study was an initial assessment of the efficacy of this determining the toxicities, response rate, time to dis- combination. ease progression, number of cycles of response, and time to treatment failure. MATERIALS AND METHODS Patients remained on primary androgen ablation Patient Eligibility during chemotherapy. Treatment consisted of 28-day Eligible patients had a histologic diagnosis of adeno- cycles with estramustine at a dose of 140 mg orally 3 carcinoma of the prostate with measurable (bidimen- times a day on Days 1-3 and 8-10 and vinorelbine sional) or evaluable (bone scan or rising PSA) disease. orally on Days 2 and 9. The estramustine dose was All patients underwent nonsteroidal antiandrogen held constant, whereas the vinorelbine dose level was withdrawal with a demonstrated rise in PSA after with- assigned using the TITE-CRM algorithm. The initial drawal. Those with PSA as their only evidence of pro- dose of vinorelbine was 50 mg/m2 based on the tox- gressive disease had to have a value Ն4 ng/mL. Eligi- icity estimates from prior studies. When a patient be- bility criteria included a granulocyte count Ն1500 came eligible for enrollment, the DLT for each dose cells/mm3, a platelet count Ն100,000 cells/mm3, bili- level was estimated based on our prior expectations of rubin Յ1.5 times the institutional upper limit of nor- toxicity and on the trial experience up to that time, mal, aspartate aminotransferase (AST) or alanine ami- and the highest vinorelbine dose with an estimated notransferase (ALT) Յ2.5 times the institutional upper DLT Յ30% was assigned to that patient. The experi- limit of normal, creatinine Յ1.2 times the institutional ence of prior patients, who had not completed the upper limit of normal, an Eastern Cooperative Oncol- 90-day acute toxicity observation window and who ogy Group (ECOG) performance status Յ2, age Ն18 had not experienced a DLT, was weighted proportion- years, and an estimated life expectancy Ն12 weeks. ally. The dose could not be escalated until at least 180 Patients were excluded if they had received prior vinca days of cumulative observation of acute toxicity in Oral Vinorelbine in Prostate Cancer/Mackler et al. 2619 patients enrolled at a particular dose level. Dose esca- surable and evaluable disease and/or a PSA Ͻ0.1 lation was restricted to 1 level between patients but ng/mL for at least 6 weeks. A partial response (PR) was there was no restriction on the number of levels that a Ն50% decrease from baseline in the sum of the the dose could be reduced. Doses could be decreased products of perpendicular dimensions of all measur- based on the accumulated toxicity data at any time able lesions and/or a Ն50% decrease in PSA from when the algorithm indicated that the 30% threshold baseline for at least 6 weeks.
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